Method for administering muscle relaxant drug

ABSTRACT

A portable neuromuscular blockade monitor having application for (i) determining the type and degree of blockade present in a patient, (ii) determining the correct time for administration of muscle-relaxant drug or antagonistic drug, or (iii) determining the amount of muscle-relaxant or antagonist to be administered, comprises a dry battery of greater than zero but up to 12V output, a transistorized oscillator circuit to convert the D.C. energy from the battery into a series of electrical pulses which are of two fixed frequencies, the first being in the range of 1 pulse per second to 1 pulse per 10 seconds and the second being in the range p  25 to 250 pulses per second, a switch means for enabling either of these frequencies to be selected and maintained, a step-up transformer and potential divider on the stepped up voltage side of the transformer and a pair of terminals to take the pulse output from the device via the potential divider.

Jan. 23, 1968 w. 5.105 ETAL 3,364,929

- METHOD FOR ADMINISTERING MUSCLE RELXANT DRUG Filed Dec. 2l, 1964 ,zo,22 3 lll 5? 45 f2( 58 56X z3 40 Z8 2Q 25 E 5M@ 6&5 N

Z5 75 HM' METER 0R A OSCILLOSCOPE ELE CTR \CQL. SUMUU TwlTcH fTETANusTwITH gb Nowoepommzme BLOCK MH @Us TunTcH g" .36. DEPoLQmzmG BLOCKINVBNTORS HHH l I l I I wlham H .NwKevmm Y BY TwlTcH TETANUSl TwmzH 90M@(mm Y ATTQRNEY` United States Patent Office 3,364,929 Patented Jan. 23,1968 3,364,929 METHOD FOR ADMINISTERING MUSCLE RELAXANT DRUG Walter S.Ide, Eastchester, and William H. Nickerson,

Tuckahoe, N.Y., assignors to Burroughs Wellcome &

Co. (U.S.A.) Inc., Tucltahoe, N Y., a corporation of New York Filed Dec.21, 1954, Ser. No. 419,949 4 Claims. (Cl. 128-172.1)

ABSTRACT OF THE DISCLOSURE A method for administering a muscle relaxantantagonist drug to counteract muscle relaxant drugs which produce bothnon-depolarizing and depolarizing blocks in patients, comprising thesteps of rst applying an electrical stimulus to the ulnar nerve and/ orthe nerve motor point muscle junction of a patient at a twitchingfrequency rate, secondly applying electrical stimulus at a tetanusfrequency rate to the same part of the patient, and thirdly reapplyingthe electrical stimulus at the frequency rate, differentiating betweenresponsiveness of the patient to said stimuli to determine the types ofneuromuscular block, and introducing an antagonist into the system ofthe patient only if the response of the patient is such that anon-depolarizing block exists.

Athe completion of surgery, it is sometimes required that the patientwho has been administered a muscle relaxant drug be stimulated by theadministration of an antagonist drug to counteract the elfects of themuscle relaxant drug. Commonly used antagonist drugs are physostigmine,eserine and edrophonium.

In some instances instead of the antagonist stimulating the patient acontinuation of the relaxation of the patient for prolonged periods hasoccurred. The prolonged period of relaxation has tended to be greaterthan that which would ordinarily occur without the administration of theantagonist, It is believed that this continuation of relaxation isrelated to the type of neuromuscular block existing in the patient.

In View of the foregoing, a new and improved apparatus for determiningthe correct time to administer muscle `antagonist drugs was required.Additionally, a new and improved method was required in order toadminister antagonists to produce a stimulation of the patient insteadof prolonging the relaxation of the patient. Accordingly, it is anobject of this invention to provide a new and improved apparatus forproviding electrical stimuli4 to differentiate between depolarizing andnondepolarizing neuromuscular blocks due to the action of certain musclerelaxant drugs.-

Another object of this `invention is to provide a new and improvedmethod of administering antagonist drugs. It is a further object of thisinvention to provide a new and improved method of determining when tointroduce muscle relaxant drugs and the administration of such drugs.

It is'an additional object of this invention to provide a new andimproved and simplified monitoring apparatus for stimulating the patientand to determine the type of neuromuscular block exhibited by thepatient.

Other objects of the invention will in part be obvious and will in partappear hereinafter.

The invention accordingly comprises the several steps and the relationof one or more of such steps with respect to each of the others, and theapparatus embodying features of construction, combinations of elementsand arrangements of parts which are adapted to eect such steps, all asexemplified in the following detailed disclosure, and the scope of theinvention will be indicated in the claims.

For a fuller understanding of the nature and objects of the invention,reference should be had to the following detailed description taken inconjunction with the accompanying drawings, in which FIG. 1 illustratesschematically a transistorized, neuromuscular block monitoring device;

FIG. 2 is an isometric representation of a splint for mounting on apatient to detect response of a patient to electrical stimuli;

FIG. 3a is a graph illustrating the sequential electrical stimuliapplied to the patient in accordance with this invention;

FIG. 3b is a graph showing the resultant response of a patient to theelectrical stimuli as a result of a non-depolarizing block affecting thenerves of the patient; and

FIG 3c is a graph illustrating a depolarizing block of a patient inresponse to electrical stimuli.

Referring now to FIGS. l and 2, a monitor oscillator or pulse generatoris shown at 20 for generating an electrical stimuli in accordance withthis invention. The pulse generator Z0 includes a relaxation oscillatorcircuit having an NPN transistor 21 with an emitter electrode 22, a baseelectrode 23 and a collector electrode 24 and a PNP transistor 25 withan emitter electrode 26, a base electrode 27 and a collector electrode28. The collector 24 of transistor 21 is coupled to the base 27 oftransistor 25. Connected between the base electrode 23 of transistor 21and collector electrode of transistor 25 is a capacitor 30. Coupledintermediate the base 23 of transistor 21 and capacitor 30 is a variableresistance network for varying the frequency of the oscillator. Theresistance network includes a switch 31 and two resistors 33 and 34,Switch 31 can be connected to either of resistors 33 and 34 to controlthe frequency of the oscillator. A source of direct current energy 34,such as a battery, is coupled at its positive terminal to emitter 26 oftransistor 25 and to the other end of resistors 33 and 34. A switch 36is provided in the line to place the DC energy source 35 in the circuit,One end of the switch is coupled to the emitter 22 and the other end ofthe switch is coupled to the battery 35. A voltage step-up transformeris generally shown at 37. Transformer has its primary winding 38 betweenthe collector 28 of transistor 25 and emitter 22 of transistor 21.

A resistor 40 coupled in series with capacitor 30 and a capacitor 41connected across winding 38 are preferably included to decreaseextraneous voltages in the circuit. The secondary winding 39 oftransformer 37 is coupled across a resistor 4S and a gas tube 46.The'resistor 45 and gas tube 46 are in parallel with a variable resistor47. The gas tube 46 indicates when the device 20 is providing a signalof a predetermined voltage level. Coupled across variable resistor 47 isa first electrode 50 and a second electrode 51 connected through aresistor 49. The electrodes may be surface-type electrodes which aresuitable for applying an electrical stimuli to the arm 52 of a patient.But, preferably, needle-type electrodes are utilized which may be of thestandard 25 gage metal needle type.

The electrodes are placed on the arm or the legs of a patient in a well-known manner such that the ulnar nerve and/or the nerve motor pointmuscle function is stimulated by the signal provided from the oscillator20. The oscillator operates as follows: upon closure of switch 36 andthe connection of switch 31 to one of resistors 33 and 34, the circuit20 will begin to oscillate. Assume, for example, that switch 31 iscoupled to resistor 34. The value of resistor 34 is selected such thatthe relaxation oscillator 2t)v will oscillate at a frequency somewhatabove zero impulses per second rbut below 30 impulses per second. Thisis commonly termed as the frequency which will produce twitching of adigital member of a limb of a patient, as for example, a finger or atoe. This will henceforth be defined as the twitching frequency. Theexact impulse frequency range to produce twitching will vary with thepatient, and therefore af requency of 20 impulses per second ispreferred. With switch 31 coupled to the resistor 34, a voltage will beapplied to transistor base 23 in such a direction as to cause transistor21 to turn on. The turning on of transistor 21 causes transistor to turnon. This causes a current to ow within the primary 3S of the transformer37. Transistors 21 and 25 will continue to conduct as long as thetransformer 37 is unsaturated. After a period of time, transformer 37becomes saturated and a voltage across secondary 39 rapidly reversesaccording to Lcnzes law. This causes a potential to be applied to base23 of transistor 21 of such a polarity as to turn off transistor 21.This, in turn, turns off transistor 25. Capacitor which charged in thereverse direction to cut olf transistor 23 due to the saturation ofinductor 37 then gradually discharges until the potential at the baseelectrode 23 of transistor 21 once again becomes of the proper polarityto turn on transistor 21 to restart the cycle.

The resultant output wave form of the oscillator is shown acrosselectrodes 50 and 51. It is to be noted that the topmost portion of theturn on cycle is slightly clipped due to the presence of gas tube 46.This gas tube ckering indicates to the observer that the impulsegenerating device 20 is operating. Assume now that the switch 31 iscoupled to resistor 33. Resistor 33 is selected such that the impulsefrequency rate will be in the order of between -120 impulses per second.In the preferred embodiment, 50 impulses per second was chosen. Thisrange of frequencies is generally referred to as the tetanus frequencyrate. The tetanus frequency reaction is observed by noticing theinvoluntary closing of a linger or a toe of a patient. The exact valuesfor the frequency rate for both tetanus and twitching is generally afunction of the patient and it is, therefore, to be understood that theranges described are only illustrative and are not limiting.

Although it is to be understood that many modifications may be made tothe above circuit, the following circuit values may be utilized toprovide an impulse generating device suitable for generating bothtetanus and twitching frequency impulses.

Transistor 21 2N335.

Transistor 25 2Nl66.

Capacitor 30 2O microfarads.

Resistor 33 5.1K ohms.

Resistor 34 330K ohms.

Battery 35 3 volts. Transformer 37 Voltage step-up of approximately 30.Resistor 40 100 ohms.

Capacitor 41 l5 microfarads.

Gas tube 46 NESlH.

The device 20 is capable of providing approximately a 90 R.M.S. outputsignal across electrodes 50 and 51 when used with a 3-volt battery asthe energy source for the circuit. This circuit is particularly usableduring the administration of an anesthesia and during operations becauseit is explosion-proof due to the low value of currents and voltagesutilized. To detect the response to the electrical stimuli providedacross the electrodes 50 and 51, a digital member such as a finger 53 ofarm 52 may be observed. This may be accomplished without the use of anyauxiliary detecting and monitoring devices shown in FIG. l. By applyinga twitching frequency signal to the electrodes 50 and 51, the twitchingsignal will produce a periodic contraction of the finger 53. Theapplication of a tetanus signal will draw the finger closed. Thus, thetwitching and tetanus signals may be observed by watching the motion ofthe finger or the toes of a patient.

The use of this information will be described at a later time in thisspecification in accordance with the method of this invention.

Although the reaction of the patient to the application of tetanus andYtwitching muscle electrical stimuli mayl be obsterved without the useof electrical equipment, it is preferred that some type of electricalmonitoring device be utilized to better assist in the recognition of thepatients response.

By the use'of a splint, generally shown at 55, which is suitable formounting on thumb 53, a device for indicating and displaying theresponse of the patient may be provided. The splint 55 comprisesresilient lat portions 55 and 57 having a bend 58 therebetween.Positioned at one end of resilient member 57 is ring 61 suitable forsurrounding the tip portion of patients thumb 53.

Attached to the other member 56 of splint 55 are clamps 62 and 63. Theseclamps are shaped like rings, but have cut out portions for permittingthe clamps to extend over the upper portion of patients thumb 53 abovethe joint. To record the bending of the splint 55, a suitable straingage 70 is mounted thereon in a position to record the pressure producedby the thumb against the splint. A strain gage, such as the type SR-4available from Baldwin-Lima Hamilton Corp., Waltham, Massachusetts, maybe used. Other types of strain or stress transducers such as strainsensitive diodes and transistors may also be utilized as well as piezoelectric devices. Strain gage 70 is connected to a suitable circuitcomprising resistor 72 and battery 73 for providing a current throughthe strain gage. The variations of the current flow through the straingage due to a change in resistance of the strain gage because of flexingof thumb 53, can then be monitored on a meter such as a voltage meter oran oscilloscope 75. Further, other display devices may be utilized, forexample, electrical type brush recorders.

Referring now to FIGS. 3a, 3b and 3c for a description of the methodaccording to this invention, assume that the patient has been injectedwith a syringe carry,

ing muscle relaxant drugs such as succinylcholine, or dimethyltubocurare. Further assume that an anesthesiologist deems it necessaryto introduce a muscle antagonistic drug to counteract the effects of themuscle relaxant drug. To determine the proper time to inject the musclerelaxant antagonist is, for example, by the use of a syringe 80 as shownin FIG. l, the neuromuscular block monitoring device 20, is turned onand set to provide electrical stimuli at a twitching frequency. Theelectrical stimuli is applied at the ulnar nerve at the wrist, elbow orat a motor junction point. It is preferable to use needle electrodeswhich may be inserted into the arm of the patient, rather than surfaceelectrodes which tend to cause slight damage tothe skin due toirritation of the electrodes after long periods of time as, for example,four hours. FIG. 3a shows the application of the electrical stimuli at atwitching frequency of about twenty impulses per second, althoughvariations may exist due to the particular patient. The response of thepatient is shown in FIGS. 3b and 3c and may be observed on theoscilloscope 75. The spikes in FIGS. 3b and 3c indicate that the patienthas reacted to the stimuli such as to produce a twitching of the digitalmember. This can also be observe-d by watching the digital memberitself. lAfter a period of time as, for example, 20 seconds monitoroscillating device 20 is then set to provide electrical stimuli at atetanus frequency. In the preferred embodiment, the monitor is set toprovide 50 impulses per seconduwh'ich is shown in FIG. 3a. Theapplication of electrical im'- pulses at tetanus frequency produces aclamping response of the patients hand or toes such that the hand ortoes tend to close during the application of the tetanus stimuli. Thismay be observed by noticing the square wave representation in FIGS. 3band 3c or, again, by watching the digital member.

In the preferred method, the tetanus is held for approximately two tothree seconds although many variations may be possible depending on theresponse of the patient. To determine the nature of the neuromuscularblock, the monitor is switched to provide electrical stimuli at thetwitching frequency once again. FIG. 3b shows the response of thepatients digit-al members to the re-application of the twitch frequencywhen there exists a non-depolarizing neuromuscular block within thepatient. This figure further shows what is generally termed post-tetanicfacilitation and which is represented by a sudden increase in theamplitude of the switch response. This has been determined to vbe theresponse by the patient to a twitch frequency after ythe application ofa tetanus frequency electrical stimuli when there exists anondepolarizing block within the patient. In FIG. 3c there is shown theresponse of the patient to the twitch electrical frequency stimuli whenthere exists a depolarizing neuromuscular block within the patient. Inthis figure it may be seen that there is no post-tetanic facilitationwhich is indicative of a depolarizing neuromuscular block.

In accordance with this invention, it has been determined that a muscleantagonist drug should be introduced into the patient only when thereexists a nondepolarizing block such as shown by the post-tetanicfacilitation of FIG. 3b. The introduction of an antagonist drug whenthere is a depolarizing block such as shown in FIG. 3c potentiates thedepolarizing block rather than counteracting the muscle relaxant drug.If the drug is administered when there is a depolarizing block, thepatient generally requires a longer period of time to overcome therelaxant drug then would normally -be required if the neuromuscularblock were permitted `to switch from a depolarizing to thenon-depolarizing neuromuscular block by itself. This will generallyoccur after a predetermined time interval h-as elapsed to permit themuscle relaxant 4drum to lose at least some of its potency. It should beunderstood that a sensor strapped to an arm or leg of the patient couldalso be utilized although a sensor strapped to a digit-al member ispreferred.

It will thus be seen that the objects set forth above, among those made4apparent from the preceding description, are eiiciently attained and,since certain changes may be made in the above article without departingfrom the scope of the invention, it is intended that all mattercontained in the above description or shown in the accompanying drawingsshall be interpreted as illustrative and not in a limiting sense.

It is also to be understood that the following claims are intended tocover all of the generic and specific features of the inventionhereindescribed, and all statements of the scope of the invention which,as a matter of language, might be said to fall therebetween.

What we claim is:

1. A method for administering a muscle relaxant antagonist drug tocounteract muscle relaxant drugs which produce both non-depolarizing anddepolarizing blocks in patients, comprising the steps of first applyingan electrical stimulus to the ulnar nerve and/ or the nerve motor pointmuscle junction of a patient at a switching frequency rate, secondlyapplying electrical stimulus lat a tetanus frequency rate to the samepart of the patient, point muscle junction of a patient at a twitchingfrequency rate, differentiating between responsiveness of the patient tosaid stimuli to determine the types of neuromuscular block, andintroducing an antagonist into the system of the patient only if theresponse of the patient is such that a non-depolarizing block exists.

2. A method for the intravenous administration of antagonistic drugs tocounteract the effects of drugs producing muscle relaxation, comprisingthe steps of sequentially applying a low amperage electrical stimuli oftwo different frequencies to a muscle motor point and/or the ulnar nerveof a patient to produce -a muscle stimulus, and administering theantagonistic drugs only when the response of the patient to theelectrical stimuli is such that a non-depolarizing neuromuscular blockexists within the patient.

3. A method for Vthe intravenous administration of antagonistic drugs tocounteract the effects of muscle relaxant drugs producing 'bothdepolarizing and nondepolarizing neuromuscular blocks in patients,comprising the steps of sequentially applying an electrical stimulus atboth twitching and tetanus frequencies to a muscle motor point and/ orthe ulnar nerve of a patient to produce a muscle stimulus, Vandadministering antagonistic drugs only when the response of the patientto the electrical stimuli is such that a non-depolarizing neuromuscularblock exists.

4. A method for administering muscle relaxation antagonistic drugs tocounteract the effects of muscle relaxant drugs which produce bothnon-depolarizing and depolarizing neuromuscular blocks in patients,comprising the steps of first applying an electrical stimulus at atwitching frequency to the ulnar nerve and/ or the muscle motor point ofa, patient, then applying an electrical stimulus at a tetanus frequencyto the ulnar nerve and/or the muscle motor point of a patient and thenreapplying an electrical stimulus at a twitching frequency to the ulnarnerve and/or the muscle motor point of a patient, and administeringantagonistic drugs only when the response of the patient is such that adepol-arizing neuromuscular `block will not be potentiated.

References Cited UNITED STATES PATENTS 2,493,155 1/1950 McMillan128-172.1 2,808,826 10/1957 Reiner et al 12S-2.1 2,830,578 4/1958 DeGroff 12S- 24.5 2,840,069 6/ 1958 Squire et al. 12S-2 3,200,814 8/1965Taylor et al. 12S-2 3,207,151 9/ 1965 Takagi 12S-2.1 3,258,007 6/1966Karpovich et a1. 12S-2 3,292,620 12/ 1966 Mahler 12S-172.1 2,979,055 4/1961 De Beer et al 12S-214 RICHARD A. GAUDET, Primary Examiner. SIMONBRODER, Examiner,

Disclaimer 3,364,929. Walter S. lele, Eastchesber, and William H.Nickerson, Tuckahoe, N.Y. METHOD FOR ADMIN ISTERING MUSCLE RELAXANTDRUG. Patent dated J an. 23, 1968. Disclaimer filed Apr. 20, 197 8, bythe assignee, Burroughs Wellcome 00. Hereby enters this disclaimer toall claims of said patent.

[Oficial Gazette June 13, 1.978.]

